Supratherapeutic Exposure

- 200 mg/kg acetaminophen (paracetamol) or more over a single 24-hour period;

- 150 mg/kg or more per 24-hour period for the preceding 48 hours;

- 100 mg/kg or more per 24-hour period for more than 48 hours.

For obese children, the weight used should be based on ideal body weight.

Aged older than 6 years ingesting

- At least 10 g or 200 mg/kg (whichever is less) over a single 24-hour period;

- At least 6 g or 150 mg/kg (whichever is less) per 24 hour period for the preceding 48 hours;

- More than 4 g per day or 100 mg/kg (whichever is less) per 24-hour period for more than 48 hours in those who also have symptoms indicating possible liver injury (e.g. abdominal pain, nausea or vomiting)

- Exposures with intent to self-harm.

For obese children, the weight used should be based on ideal body weight.

- If this concentration is less than 1,000 umol/L (150 mg/L) the child may safely be discharged. Otherwise, repeat the measurement at 4 hours and if above the paracetamol treatment nomogram line administer acetylcysteine.

- If this concentration is below the nomogram line, the patient does not require acetylcysteine;

- If this concentration is above the nomogram line, immediately commence a full course of acetylcysteine;

- If this concentration will not be available within 8 hours of ingestion, immediately commence a full course of acetylcysteine. This treatment can then be halted if the result subsequently returns below the nomogram line.

Ingestion of modified release formulations

If the ingestion is above the intervention level, immediately commence a full course of acetylcysteine, then:[1]

Measure:

Serum acetaminophen (paracetamol) concentration at least 4 hours post-ingestion and a second concentration 4 hours following the first:

- If these concentrations are both below the paracetamol treatment nomogram line, and the second concentration less than the first, the acetylcysteine infusion may be halted. Otherwise, the full treatment course must be completed.

- If the serum acetaminophen (paracetamol) concentration is below the paracetamol treatment nomogram line and the ALT is less than 50 U/L, then the acetylcysteine infusion can be halted and no further medical treatment is necessary.[1]

- If the serum acetaminophen (paracetamol) concentration is above the paracetamol treatment nomogram line or the ALT greater than 50 U/L, then complete a full course of acetylcysteine.[1]

- If the serum acetaminophen (paracetamol) concentration is less than 66 umol/L (10 mg/L) and the ALT is less than 50 U/L, then the infusion can be halted and no further medical treatment is necessary.[1]

- If the serum acetaminophen (paracetamol) concentration is greater than 66 umol/L (10 mg/L) or the ALT is greater than 50 U/L, then complete the full course of acetylcysteine.[1]

-Serum acetaminophen (paracetamol) is < 66 umol/L (< 10 mg/L) and ALT < 50 U/L, then the infusion can be halted and no further medical treatment is necessary.[1]

Observation Period

Observation at Home

No observation is required for those patients with ingested doses or serum acetaminophen (paracetamol) determinations below the intervention levels. However, review is warranted should nausea, vomiting, or abdominal pain occur after discharge, particularly if within 24 to 48 hours after the ingestion.

Medical Observation

Medical observation of asymptomatic patients is not required provided serum acetaminophen (paracetamol) investigation is undertaken and the concentration is below the appropriate intervention level.

Admission Criteria

Patients requiring intervention for acute acetaminophen (paracetamol) overdose should be appropriately decontaminated and managed in a medical facility able to rapidly determine serum acetaminophen (paracetamol) and provide acetylcysteine.

Referral to an intensive care unit and/or liver transplant unit may be required in severe poisoning.

TREATMENT

TREATMENT SUMMARY

Decontamination with activated charcoal is recommended in cooperative adults within 2 hours of ingestion of (solid) immediate-release forms, or within 4 hours of ingestion of either modified-release forms or greater than 30 g of acetaminophen (paracetamol).[2][1]

Following acute overdose, assessment of serum acetaminophen (paracetamol) concentration between 4 to 8 hours and use of the paracetamol treatment nomogram is necessary to determine requirement for the antidote acetylcysteine. If a result is not available within this timeframe acetylcysteine should be commenced and is considered beneficial at any time post-ingestion.[3] Acetylcysteine administration following supratherapeutic/chronic ingestions is dependent on dose and investigations.

In cases of massive acetaminophen (paracetamol) ingestion (greater than 50 g or serum concentrations greater than twice the nomogram line) doubling the final (16 hour) acetylcysteine infusion is recommended.[1] Hemodialysis may be beneficial in severe poisoning with very high blood concentrations and particularly if acetylcysteine is unavailable.[4]

Supportive care includes the continued use of acetylcysteine, monitoring of major organ function, and further management as indicated. Use of sedating drugs is not recommended due to their impact on the assessment of mental function/encephalopathy. Acute hepatic and renal failure are well recognized concerns. Most complications are a consequence of hepatic failure and rarely occur in its absence.

The International Normalized Ratio (INR) is greater than 3 at 48 hours or 4.5 at any time after overdose

Or

Oliguria or creatinine is greater than 200 umol/L (2.2 mg/dL)

Or

Persistent acidosis (pH less than 7.3) or arterial lactate greater than 3 mmol/L

Or

Systolic hypotension with a blood pressure less than 80 mmHg, despite resuscitation

Or

Hypoglycemia

Or

Severe thrombocytopenia

Or

Encephalopathy of any degree, or any alteration of consciousness (Glasgow Coma Scale less than 15) not associated with co-ingestion of sedatives

Early discussion with a liver transplant unit is essential. Advice may be given and a decision to transport dependent upon results. In general it is considered desirable to transport patients prior to development of grade 2 encephalopathy.

EMERGENCY STABILIZATION

Emergency Stabilization Should Not Be Required

Emergency stabilization of patients following recent ingestion of acetaminophen (paracetamol), solely, is highly unlikely to be necessary. However, massive overdose may lead to early decline in level of consciousness and/or lactic acidosis.[5] Immediate attention should be given to the airways, assessment of blood glucose, and supportive care.[1] Definitive treatment is provided by the antidote acetylcysteine, with hemodialysis possibly indicated.[4] Carefully consider coingestant(s) or non-toxicological causes.

DECONTAMINATION

Ingestion

Single Dose Activated Charcoal

Gastrointestinal decontamination is not indicated in any pediatric (< 6 years old) patient following acetaminophen (paracetamol) overdose.[1]

Gastrointestinal decontamination with activated charcoal is only indicated:[1]

In co-operative adult patients

If the formulation is a solid (e.g. tablets, capsules)

If at least 10 g or 200 mg/kg (which ever is lower) is ingested

Within 2 hours of the overdose for standard release formulations

Within 4 hours of the overdose for modified release formulations (patients may benefit from activated charcoal beyond 4 hours following large ingestions)

If at least 30 g is ingested

Within 4 hours of the overdose for standard release formulations

Further decontamination with activated charcoal may be necessary for co-ingestants.

ANTIDOTE(S)

Acetylcysteine

Acetylcysteine is the treatment of choice for acetaminophen (paracetamol) overdose, and its intravenous use considered preferable.[7] When administered within eight hours of acetaminophen (paracetamol) ingestion it is almost completely effective in preventing death.[8] Use beyond this time is also beneficial and recommended.[3]

In the case of modified release formulations, acetylcysteine may need to be continued after the initial 21 hour infusion.

Indications

Intra-venous acetylcysteine infusion is indicated as outlined in the following links:

Dose and Administration

While acetylcysteine is recommended to be administered intravenously in 5% dextrose in water, 1/2 normal (0.45%) saline may be substituted if necessary.[9] It is recommended that acetylcysteine dose for adults be calculated for actual body weight rounded up to the nearest 10 kg with a ceiling weight of 110 kg.[1]

In the case of massive overdose (those whose acetaminophen (paracetamol) concentration is more than double the nomogram line) it is recommended that the final infusion over 16 hours is doubled to 200 mg/kg.[1]

Antidote Endpoint

Acute

Recommended investigations according to time from acetaminophen (paracetamol) ingestion to acetylcysteine treatment[1]

* NOTE: If symptoms of hepatotoxicity (e.g. nausea, vomiting, abdominal pain or tenderness) then repeat ALT. Or if initial concentration more than double the nomogram line, then repeat ALT and paracetamol concentration at the completion of acetylcysteine.

Patients who have ALT > 50 U/L following completion of initial acetylcysteine require acetylcysteine to be continued at the rate of the last infusion stage (100 mg/kg acetylcysteine over 16 hours or 150 mg/kg/24 hours).[1]

Continue acetylcysteine until the patient is clinically improving, ALT is decreasing, INR is improving and < 2, and the acetaminophen (paracetamol) concentration is less than 66 umol/L (10 mg/L).[1][10]

Serum acetaminophen (paracetamol) is <66 umol/L (<10 mg/L) and ALT is less than 50 U/L, then the infusion can be halted and no further medical treatment is necessary.[1]

Precautions

Pregnancy

Acetylcysteine should be administered to pregnant patients following the standard adult regimen. Transplacental transport of acetylcysteine is not thought to be clinically significant,[11] however, delay in initiation of acetylcysteine treatment is associated with increased incidence of spontaneous abortion and fetal death.[12] Acetylcysteine is not considered teratogenic.[13]

Adverse Effects

Anaphylactoid Reaction

Six to 23% of patients receiving IV acetylcysteine develop an anaphylactoid reaction.[14][15] These do not represent an immunological (allergic) reaction; rather, they are thought due to a direct dose-dependent effect on histamine release and generally occur within the first two hours of an infusion.

History of previous anaphylactoid reaction to acetylcysteine does not contraindicate use. If there is concern of recurrence of the reaction the patient may be pre-treated 15 minutes before commencement of the infusion with an antihistamine.[16]

Effects range from mild flushing to urticaria, angioedema, or bronchospasm. Hypotension may occasionally occur. Asthmatics appear more at risk. However, effects are usually easily managed and there is no reason to withhold acetylcysteine from any patient when indicated.[16]

Hyponatremia

Hyponatremia has been reported in children if administered acetylcysteine in 5% dextrose following adult protocols for dilution of infused dose.[17]

INR

Increased International Normalized Ratio (INR) in the absence of acetaminophen-induced hepatic injury is relatively common.[18][19][20] It is important that increased INR alone (below 2) is not misinterpreted as evidence of acetaminophen-induced hepatic injury, as this may lead to unnecessarily prolonged acetylcysteine administration.[19]

ENHANCED ELIMINATION

Hemodialysis

In the majority of cases NAC is the only specific treatment required as acetaminophen (paracetamol) has a high endogenous clearance. However, acetaminophen (paracetamol) is moderately dialyzable,[21][22][23] and extracorporeal techniques may be beneficial in excessively large overdoses if NAC cannot be administered or where there is mitochondrial paralysis or other signs of severe poisoning.

Intermittent hemodialysis is recommended in any of the following situations:[4]

- If the patient presents with an altered mental status, metabolic acidosis, an elevated lactate:

Intermittent hemodialysis is preferred but hemoperfusion or continuous renal replacement therapy are acceptable alternatives if hemodialysis is not available. Exchange transfusion is an adequate alternative to hemodialysis in neonates.[4]

As NAC is dialyzable, NAC administration should be increased during hemodialysis. Up to 25% of NAC is removed by continuous renal replacement therapy and up to 50% with intermittent hemodialysis. The increase should match the expected losses from the extracorporeal technique.[4] It is recommended the dose is doubled while undergoing hemodialysis.[24][25]Hemodialysis should continue until clinical improvement is apparent.[4]

SUPPORTIVE CARE

Monitoring

The following is initially recommended, however further monitoring will be required should toxic effects become apparent.

Liver function tests:

Alanine aminotransferase (ALT)

Aspartate aminotransferase (AST)

International Normalized Ratio (INR)

Serum electrolytes:

Phosphate

Urinalysis

Renal function

Creatinine

Blood glucose

Full blood count

Arterial blood gases

Mental function

Hepatic

Acute Hepatic Failure

Acute hepatic failure developing from the third to sixth day following acetaminophen (paracetamol) overdose is a major concern. It is characterized by highly elevated hepatic transaminase levels (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) but with little rise in alkaline phosphatase, and modest increase in plasma bilirubin (with the exception of chronic alcoholics and those with severe hepatic damage).[26] As hepatic function deteriorates International Normalized Ratio (INR) rises, and a range of complications develop including coagulopathy, hypoglycemia, metabolic acidosis, and hepatic encephalopathy. Acetylcysteine administration should be continued regardless of time after overdose as it appears beneficial even once hepatic failure is apparent.[3]

Renal

Acute Renal Failure

Acetaminophen (paracetamol) can be nephrotoxic, even in the absence of hepatotoxicity (though this is uncommon).[27] Onset ranges from 2 to 5 days after overdose, with peak serum creatinine measured at 3 to 16 days.[26][28] The cause is acute tubular necrosis and may be more common in those with risk factors to acetaminophen (paracetamol) toxicity.[29] While the insult is typically reversible, interim support with hemodialysis may be required. Urea production will be reduced in the presence of hepatic failure and is therefore not a good index of renal function.[26] Advice should be sought from a liver transplant unit if creatinine is greater or equal to 200 umol/L (2.2 mg/dL).[30]

Hematologic

Coagulopathy

Coagulopathy is a common occurrence following acute hepatic failure. Coagulopathy should be managed in conjunction with hepatic failure. Alteration of coagulopathy is often seen before peak hepatic dysfunction.[31]

Patients should be monitored for increased International Normalized Ratio (INR).

Thrombocytopenia

Common in those with acetaminophen (paracetamol) induced acute hepatic failure and likely related to disseminated intravascular coagulation,[32] but rarely of significance in those without hepatotoxicity.[33] Monitoring for thrombocytopenia should be undertaken if acute hepatic failure develops. Platelets may be administered if the count is less than 50 x 10 to the power of 9/L.

Monitor:

White blood cell count

Platelet count

Manage thrombocytopenia using standard treatment protocols.

Hemolysis

Patients with glucose-6-phosphate dehydrogenase deficiency may be at risk of hemolysis following acetaminophen (paracetamol) overdose.[34][35][36]

Patients should be monitored for evidence of hemolysis:

Jaundice

Pallor

Hemoglobinuria

Anemia

Peripheral blood smear

Reticulocytosis

Heinz bodies

Cell fragments

Whole blood hemoglobin (may be decreased)

Free plasma hemoglobin (may be increased)

Serum haptoglobin (may be decreased)

Spherocytes (may be present)

Red cell glucose-6-phosphate dehydrogenase testing may be indicated

Follow standard protocols for the management of hemolysis.

Cardiovascular

Hypotension

Hypotension may follow acetaminophen (paracetamol) ingestion[37] and is usually related to hepatotoxicity.

Patients should be closely monitored for onset of hypotension. Should this occur in association with hepatic failure, invasive hemodynamic monitoring is recommended as part of management.

Cardiotoxicity

In those with severe acetaminophen (paracetamol) poisoning, an electrocardiogram (ECG) during the first 48 hours may show minor non-specific S-T changes and T-wave flattening with U-waves, possibly related to hypophosphatemia. Serious cardiovascular abnormalities and hypotension, if they occur, are likely secondary to acute hepatic failure.[26]

Patients suffering acute hepatic failure from acetaminophen (paracetamol) toxicity should be monitored with an ECG for cardiac dysrhythmia.

Metabolic

Metabolic Acidosis

Metabolic (lactic) acidosis following acetaminophen (paracetamol) overdose is typically a consequence of hepatic failure and should be treated as such. However, it has been described following massive overdose (associated with central nervous system depression) in the absence of clinical liver failure.[38][39] In such cases acidosis is considered due to early mitochondrial inhibition following glutathione depletion and before cellular damage.[40] Patients should be monitored for onset of acidosis if presenting with either very high acetaminophen (paracetamol) concentrations or depressed level of consciousness. Hemodialysis is recommended in patients presenting with an altered mental status, metabolic acidosis, and an elevated lactate with very high blood acetaminophen (paracetamol) concentrations, especially if NAC cannot be administered.[4] If hepatic injury is present, advice should be sought from a liver transplant unit if there is persistent acidosis (pH less than 7.3) or arterial lactate greater than 3 mmol/L.[1]

Monitor:

Arterial blood gases (pH, bicarbonate, pCO2, pO2)

Plasma lactate

Base excess

Follow standard protocols for the management of metabolic acidosis.

Hypoglycemia

Hypoglycemia has been reported[41] and is most likely a consequence of acute hepatic failure and should be managed in conjunction with this condition. Patients with severe hepatic failure should be monitored for hypoglycemia.

Hypophosphatemia

Hypophosphatemia may occur as a result of either hepatic or renal failure due to acetaminophen (paracetamol) overdose,[42] but would appear more likely due to the later.[43]

Monitor serum phosphate

Treat following standard protocols for hypophosphatemia.

Respiratory

Pulmonary Edema

Acute lung injury has been reported as common in those suffering acetaminophen (paracetamol) induced fulminant hepatic failure.[44]

Non-cardiogenic pulmonary edema may manifest with desaturation and pulmonary rales. On occasion frothy, pink sputum may be apparent. Monitoring for this condition should include:

Chest auscultation

Oxygen saturations

Arterial blood gases

Chest X-ray

Follow standard protocols for the management of non-cardiogenic pulmonary edema.

Gastrointestinal

Pancreatitis

Pancreatitis occurs rarely following acetaminophen (paracetamol) overdose, and appears related to prior alcohol intake or hemorrhage rather than direct acetaminophen (paracetamol) toxicity. Patients should be monitored for pancreatitis if dehydration is suspected, or their presentation is late.[33]

In other cases continued acetylcysteine infusion (100 mg/kg per 16 hours) is required until improvement.[45] If continued infusion is required discharge may occur when liver function tests, International Normalized Ratio (INR), and creatinine are shown to be normalizing.

Discharge after development of hepatic or renal failure, or other consequences, should follow standard protocols for those conditions.

FOLLOW UP

Standard protocols should be used for follow-up of patients suffering hepatic or renal failure, including advice that patients should abstain from alcohol for six weeks to allow regeneration of the liver.

Patients should be referred for psychiatric assessment as appropriate.

PROGNOSIS

Full recovery from both hepatic and renal damage due to acetaminophen (paracetamol) toxicity is usual, but not inevitable.

SIGNS AND SYMPTOMS

Initial manifestations of acetaminophen (paracetamol) intoxication may be absent or may only include gastrointestinal effects, malaise, pallor, and diaphoresis.[46][47] Rarely, following massive overdose, there may be an initial metabolic acidosis and coma.[5][38]

Hepatic damage is a common feature of acetaminophen (paracetamol) toxicity and further signs and symptoms become apparent if hepatotoxicity develops. As time after overdose increases signs and symptoms associated with acute hepatic failure including right upper quadrant tenderness, hypotension, acidosis, coagulopathy, encephalopathy, and hypoglycemia may develop.[47][48][49] Jaundice is not evident as an early sign but develops as hepatic failure progresses.[47] Additionally, an initial increase in INR can be seen in the first 24 to 48 hours which appears to result from an inhibition of the activation of vitamin K dependent coagulation factors.[50] Later, coagulopathy is typically a result of liver failure.

Renal failure associated with acetaminophen (paracetamol) overdose may rarely appear acutely, or more usually over a period of days and in association with hepatotoxicity/failure.[33] Cardiovascular concerns are rarely an acute consequence of poisoning, but hypotension and myocardial injury may appear in patients with fulminant hepatic failure as part of multisystem organ failure.[51]

Onset/Duration of Symptoms

Acetaminophen (paracetamol) in the form of liquid formulations and oro-dispersable tablets are more quickly absorbed than standard tablets,[52] so may alter the onset of symptoms. Modified release tablets may additionally alter the time course of toxicity.

Four phases of acute acetaminophen (paracetamol) toxicity have been described.[46]

Phase 1 (0.5 to 24 hours after overdose): During the first 24 hours following acute overdose a patient may have few if any signs or symptoms. However, they may demonstrate malaise, anorexia, nausea, vomiting, pallor, and diaphoresis.[46][47]Rarely, following massive overdoses, metabolic acidosis and coma may occur in this phase as a direct toxic effect.[5][38]

Dermatologic

Hematologic

CHRONIC EFFECTS

Symptoms in chronic situations are broadly similar to acute ones. Heptotoxicity and its complications are the major concern.[86][85]

TOXICITY

HUMAN

Acute

Child

Children appear less susceptible to hepatotoxicity from acetaminophen (paracetamol) than adults. Toxicity following pediatric exploratory ingestions is rare.[1][87] However, the exact toxic dose is still subject to debate. Oro-dispersible formulas may present an increased risk over standard tablets due to their near immediate disintegration when in contact with saliva.[52]

Medical attention is warranted for ingestions of 200 mg/kg or more in children 6 years or under, or the lesser of 10 g or 200 mg/kg in children over 6 years.[1][88]

Adult

Acetaminophen (paracetamol) induced hepatotoxicity may occur in adults after large doses. In a study of patients over 12 years of age, a single dose of less than 12 g can cause severe hepatotoxicity, and death has occurred with doses over 15 g.[89]

Medical attention is warranted following ingestions of the lesser of 10 g or 200 mg/kg acetaminophen (paracetamol).[1][88]

Case Studies

8 g modified release Acetaminophen (paracetamol)(ingested)

35 year female: 4 hour acetaminophen concentration was 695 umol/L, 6 hour concentration was 950 umol/L. Asymptomatic at all times

24 year female (alcohol abuse suspected): developed nausea, vomiting, and anorexia within hours of ingestion. Presented at hospital 2 days later with abdominal pain and discharged soon after. Nausea worsened and hematemesis occurred. On second admission was comatose and tachycardic. Later developed centrilobular hepatic necrosis, renal tubular necrosis, encephalopathy, hypotension, and hypoglycemia

Chronic

Chronic overdose, for example ingestion of several high 'therapeutic' doses of acetaminophen (paracetamol) over 1 to 2 days, or multiple minor overdoses over a short period of time, may produce moderate or even severe hepatic damage.[86]

The staggered dose required to produce acetaminophen (paracetamol) toxicity has yet to be established.

Medical attention is warranted for children 6 years or under who ingest 200 mg/kg or more over a single 24 hour period, 150 mg/kg per 24 hours for the preceding 48 hours, or 100 mg/kg per 24 hours more than 48 hours.[1]

Medical attention is warranted for adults and children over 6 years who ingest the lesser of 10 g or 200 mg/kg or more over a single 24 hour period, the lesser of 6 g or 150 mg/kg per 24 hours for the preceding 48 hours, or the lesser of 4 g or 100 mg/kg per 24 hours for more than 48 hours in patients with symptoms indicating possible liver injury e.g. abdominal pain or nausea or vomiting.[1]

Child

Case Studies

7 month male (pre-existing fever, it was unknown about the high dose of acetaminophen at the initial time of presentation at hospital): vomiting, tachycardia, drowsiness, melena, and abdominal distension. Six hours after admission developed seizures, hypoglycemia, increased liver enzymes, increased INR, and increased total bilirubin. Later developed metabolic acidosis and shock

Adult

Case Studies

17,000 mg acetaminophen (paracetamol) over 4 days and 1 morning(ingested)

45 year male (HIV positive, hepatitis B, Hepatitis C, IV heroin abuse, and starvation over the period of acetaminophen administration): worsening weakness, malaise, and nausea over the 4 days of acetaminophen ingestion, and hepatotoxicity

The mother required re-operation due to post-operative complications. The fetus was viable at this stage. From post-operative day 6 to 17 the fetus developed ascites, pericardial effusion, ventriculomegaly, hydrocephalus, subarachnoid fluid, compression of the cavum septum pellucidum, and lateral herniation of the brain. The fetus was electively aborted. The mother survived[94]

ANIMAL

Cats

Cats are very susceptible to toxicity as they have limited ability to metabolize acetaminophen (paracetamol) due to a limited capacity of their glucuronidation pathway and/or saturation of their sulfate conjugation pathway.[95] As little as 50 to 60 mg/kg orally may be toxic.[96]

Signs may occur within a few hours of ingestion and include depression, anorexia, vomiting, cyanosis, edema of the face and extremities, methemoglobinemia, dyspnea, hepatotoxicity, and death. Hematuria and hemoglobinuria usually appear first, when blood methemoglobin levels are around 20%.[96] Cats typically do not develop major hepatotoxicity although this may be due to cats dying from hypoxia secondary to methemoglobinemia at doses that are too low to produce hepatic necrosis.[96]

Dogs do have the ability to metabolize acetaminophen (paracetamol), however, methemoglobinemia is a concern as is hepatic damage. Toxic doses for dogs are probably greater than or equal to 150 mg/kg.[96]

Signs develop within one to two hours of ingestion and are progressive, consisting of anorexia, salivation, vomiting, hypovolemia, depression, methemoglobinemia, hematuria or hemoglobinuria, and edema of the face and/or paws. Muscle tremors or rarely seizures may occur, possibly through triggering of latent epilepsy. Hematuria and hemoglobinuria usually appear first, when blood methemoglobin levels are around 20%. Signs may persist 12 to 48 hours. Acute hepatic failure may follow initial signs. Death may occur 18 to 36 hours post ingestion.[96]

BIOLOGICAL LEVELS - TOXIC

SI Unit Conversion

To convert an acetaminophen (paracetamol) concentration expressed in mg/L into umol/L:

Multiply the mg/L by 6.6155

To convert an acetaminophen (paracetamol) concentration expressed in umol/L into mg/L:

Multiply the umol/L by 0.1512

Outside of the United States most laboratories report acetaminophen (paracetamol) concentration expressed in umol/L. It is important to check what units your laboratory uses before referring to the nomogram.

Toxic Serum Level

A serum concentration versus time curve or Acetaminophen (Paracetamol) Nomogram has been constructed to provide an indication of potentially hepatotoxic acetaminophen (paracetamol) serum concentrations. Note this graph displays the acetaminophen (paracetamol) concentration in both umol/L and mg/L.

REPRODUCTION

PREGNANCY

Acetaminophen (paracetamol) is routinely used during all stages of pregnancy for pain relief and to lower elevated body temperature. In therapeutic doses, it probably is safe to use in the short term.[101]

Acetaminophen (paracetamol) crosses the placenta and is transformed by fetal hepatocytes into the toxic metabolite.[102] While it is felt the fetus is less susceptible to hepatic damage than adults,[102] an association is indicated between maternal first trimester overdose and abortion within 2 to 3 weeks.[103] Though transplacental transport of acetylcysteine is not thought to be clinically significant,[11] delay in initiation of acetylcysteine treatment is associated with increased incidence of spontaneous abortion and fetal death.[12] Neither acetaminophen (paracetamol) nor acetylcysteine appears teratogenic and termination of pregnancy is not indicated in most circumstances after acetaminophen (paracetamol) overdose.[13]

A 19 week pregnant female who was ingesting 6 g acetaminophen daily for 2 weeks developed hepatic encephalopathy and fulminant hepatic failure. As the fetus was initially deemed viable, maternal liver transplant took place. Due to maternal complications a further surgery was required. Six days post-operation the fetus developed complications of fetal ascites and pericardal effusion, and later developed ventriculomegaly, hydrocephalus, subarachnoid fluid, compression of the cavum septum pellucidum, and lateral herniation of the brain. The brain injury was deemed to be non-conducive with life and the fetus was aborted.[94]

LACTATION

The American Academy of Pediatrics considers acetaminophen (paracetamol) to be compatible with breast-feeding.[108]

TOXIC MECHANISM

At therapeutic doses, 90% of acetaminophen (paracetamol) is converted to non-toxic glucuronide and sulfate conjugates, and 5% is excreted in the urine unchanged. The other 5% is oxidized in the liver by P450 2E1, P450 1A2 and P450 3A4 to N-acetyl-p-benzoquinoneimine (NAPQI).[109] At therapeutic amounts glutathione binds with NAPQI to form a non-toxic conjugate. In overdose, glucuronide and sulfate conjugation becomes saturated and an increased proportion of NAPQI is formed. Glutathione levels are depleted, as the demand for glutathione is higher than the formation of glutathione.[110] This means that NAPQI remains in its toxic form in the liver and can bind to cysteine containing macromolecules.[111] This can cause hepatocellular damage, in particular centrilobular necrosis.[46] The exact mechanism of damage in the liver is unknown. NAPQI can also be produced in the kidney leading to renal damage.[112]

Both acetaminophen (paracetamol) and NAPQI are capable of inhibiting hepatic mitochondrial respiration,[113] generally following massive ingestions.[38][24]

THERAPEUTIC DRUG INFORMATION

INDICATIONS

This is intended as a guide only. For a more comprehensive list, refer to manufacturer's information.

PHARMACOLOGICAL ACTION

The pharmacological action of acetaminophen (paracetamol) is not fully understood. It has been hypothesized that the mechanisms involved for producing analgesia and antipyrexia are similar to that of the salicylates but with only weak anti-inflammatory effects.

It is known that acetaminophen (paracetamol) selectively inhibits prostaglandin synthesis, predominantly in the central nervous system and to a lesser extent in the periphery.[121] Acetaminophen (paracetamol) also lowers body temperature by acting on the hypothalamus to increase vasodilatation and peripheral blood flow to aid heat dissipation. This occurs largely in patients with a fever, with little change in body temperature in subjects with normal body temperature. Acetaminophen (paracetamol) is also a weak inhibitor of the enzyme cyclo-oxygenase, but only in the presence of a high concentration of peroxides.[122]

Disclaimer

All information contained on this database is as accurate and up-to-date as our resources allow. Since the University of Otago, the New Zealand National Poisons Centre and Intergen cannot anticipate or control the conditions under which this information may be used, each user should view the information in the specific context of the intended application.

The University of Otago, the New Zealand National Poisons Centre and Intergen will not be responsible for damages of any nature resulting from use or reliance upon this information.